Traditional Chinese medicine composition for synergistically enhancing anti-hepatoma curative effect of PD-1 inhibitor and reducing toxic and side effects and application of traditional Chinese medicine composition

Abstract

The invention belongs to the technical field of traditional Chinese medicine. More specifically, the invention relates to a traditional Chinese medicine composition for synergistically enhancing the anti-hepatoma curative effect of a PD-1 inhibitor and reducing toxic and side effects and application of the traditional Chinese medicine composition. The research finds that the traditional Chinese medicine composition and a PD-1 inhibitor are combined for use, so that a remarkable anti-tumor effect can be generated. Clinical research proves that when the traditional Chinese medicine composition is combined with the PD-1 inhibitor, the objective remission rate can be increased, clinical symptoms (such as liver region pain, weakness and poor appetite) of patients can be improved, the life quality can be further improved, and meanwhile, the adverse reaction related to immunotherapy can be effectively reduced. The traditional Chinese medicine composition provided by the invention solves the clinical problems of low effective rate and large toxic and side effects of PD-1 inhibitor single-drug treatment through a multi-target regulation effect, provides a safer and more effective scheme for immunotherapy of liver cancer, and has good clinical application prospects and popularization values.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of traditional Chinese medicine. More specifically, it relates to a traditional Chinese medicine composition for synergistically enhancing the anti-hepatocarcinoma efficacy of PD-1 inhibitors and reducing the side effects thereof, and the application thereof. BACKGROUND

[0002] Programmed death receptor-1 (PD-1) inhibitors have become an important means for treating advanced primary hepatocarcinoma (hereinafter referred to as hepatocarcinoma) by blocking the PD-1 / PD-L1 signaling pathway and activating the immune response ability of T cells against tumors. Although it has shown certain efficacy in prolonging the survival of patients, clinical studies have shown that the objective response rate (ORR) of PD-1 inhibitor monotherapy is only 15%~20%, and the efficacy of some patients is limited due to the presence of primary or acquired drug resistance. In addition, immune checkpoint inhibitors are often accompanied by immune-related adverse events (irAEs), such as immune hepatitis, pneumonia, and thyroid function abnormalities, which can lead to treatment interruption in severe cases, limiting their clinical application.

[0003] Traditional Chinese medicine has a unique advantage of multi-component and multi-target regulation in tumor treatment, and is believed to be able to enhance the efficacy of PD-1 inhibitors while reducing their side effects. Studies have shown that some traditional Chinese medicine ingredients can enhance anti-tumor immune response by regulating the tumor immune microenvironment, such as ginsenoside Rg3, which can increase the proportion of CD4+ and CD8+ T cells and enhance T cell-mediated immune response; baicalein was found to down-regulate the expression of PD-L1 in tumor cells.

[0004] Currently, PD-1 inhibitors are often combined with anti-angiogenic drugs for hepatocarcinoma treatment in clinical practice, although there is a certain synergistic effect, but still faces problems such as toxicity superposition and high treatment cost. Traditional Chinese medicine compounds have shown certain auxiliary potential in empirical treatment, but still have obvious limitations in terms of inconvenient dosage forms (such as decoction which is not easy to carry), unclear mechanism of action, lack of standardization, etc., which restrict their widespread application. Therefore, it is of great clinical significance and application prospect to develop a traditional Chinese medicine preparation with clear mechanism, definite efficacy, convenient use and effective synergistic effect with PD-1 inhibitors for treating hepatocarcinoma. SUMMARY

[0005] The present application aims to overcome the defects of poor effect and large side effects of existing PD-1 inhibitor monotherapy for hepatocarcinoma, and provides a traditional Chinese medicine composition which can be used in combination with PD-1 inhibitors for treatment, not only improving the objective response rate and improving the clinical symptoms of patients, but also effectively reducing the immune therapy-related adverse reactions.

[0006] The first object of the present application is to provide a traditional Chinese medicine composition.

[0007] A second object of the present application is to provide a traditional Chinese medicine preparation.

[0008] A third object of the present application is to provide uses of the above-mentioned traditional Chinese medicine composition and traditional Chinese medicine preparation.

[0009] A fourth object of the present application is to provide a medicine for treating liver cancer.

[0010] The above objects of the present application are achieved by the following technical solutions. The present application provides a traditional Chinese medicine composition, which comprises the following raw materials in parts by weight: Radix Codonopsis 20-40 parts, Radix Notoginseng 30-60 parts, Radix Salviae Miltiorrhizae 10-20 parts, Curcuma zedoary 10-20 parts, Radix Lamiophlomis 10-20 parts, Rhizoma Corydalis 15-20 parts, Carapax Trionycis Acetate 20-40 parts, Rhizoma Atractylodis Macrocephalae 15-30 parts, Poria 20-30 parts, Herba Sarcandrae 30-60 parts, Radix Paeoniae Alba 10-20 parts, Radix Paeoniae Rubra 10-20 parts, Fructus Corni 10-20 parts, Folium Lophatheri 10-15 parts, and Radix Glycyrrhizae 5-10 parts.

[0011] As an alternative embodiment, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: Radix Codonopsis 20-30 parts, Radix Notoginseng 30-45 parts, Radix Salviae Miltiorrhizae 10-20 parts, Curcuma zedoary 10-20 parts, Radix Lamiophlomis 10-20 parts, Rhizoma Corydalis 15-20 parts, Carapax Trionycis Acetate 20-40 parts, Rhizoma Atractylodis Macrocephalae 15-30 parts, Poria 20-30 parts, Herba Sarcandrae 30-45 parts, Radix Paeoniae Alba 10-20 parts, Radix Paeoniae Rubra 10-20 parts, Fructus Corni 10-20 parts, Folium Lophatheri 10-15 parts, and Radix Glycyrrhizae 5-10 parts.

[0012] As an alternative embodiment, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: Radix Codonopsis 20 parts, Radix Notoginseng 30 parts, Radix Salviae Miltiorrhizae 15 parts, Curcuma zedoary 15 parts, Radix Lamiophlomis 10 parts, Rhizoma Corydalis 15 parts, Carapax Trionycis Acetate 30 parts, Rhizoma Atractylodis Macrocephalae 15 parts, Poria 20 parts, Herba Sarcandrae 30 parts, Radix Paeoniae Alba 10 parts, Radix Paeoniae Rubra 15 parts, Fructus Corni 15 parts, Folium Lophatheri 10 parts, and Radix Glycyrrhizae 6 parts.

[0013] As an alternative embodiment, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: Radix Codonopsis 30 parts, Radix Notoginseng 45 parts, Radix Salviae Miltiorrhizae 15 parts, Curcuma zedoary 15 parts, Radix Lamiophlomis 15 parts, Rhizoma Corydalis 15 parts, Carapax Trionycis Acetate 30 parts, Rhizoma Atractylodis Macrocephalae 15 parts, Poria 25 parts, Herba Sarcandrae 45 parts, Radix Paeoniae Alba 15 parts, Radix Paeoniae Rubra 15 parts, Fructus Corni 15 parts, Folium Lophatheri 10 parts, and Radix Glycyrrhizae 6 parts.

[0014] As an alternative embodiment, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: Dangshen 40 parts, Beiqi 60 parts, Danshen 20 parts, E Zha 20 parts, Bayue Zha 20 parts, Yanshuo 20 parts, Vinegar Biejia 40 parts, Baizhu 30 parts, Fuling 30 parts, Baihuashexiangcao 60 parts, Danpi 20 parts, Baishao 20 parts, Shanzhu 20 parts, Faxia 20 parts, Chenpi 15 parts, and Muzegancao 10 parts.

[0015] The prescription of the traditional Chinese medicine composition in the present application is as follows: 1. Monarch drug: Dangshen + Beiqi Function: Both are monarch drugs, and are used in large amounts to invigorate the spleen and nourish the stomach, tonify the middle and strengthen the body immunity, and provide a "tonifying" basis for the synergistic PD-1 inhibitor. Modern research shows that the polysaccharide components of both can regulate T cell activity and potentially enhance immune therapy response.

[0016] 2. Minister drug: Danshen + E Zha + Bayue Zha, Yanshuo, and Vinegar Biejia Function: Danshen + E Zha + Bayue Zha can soothe the liver and move qi, promote blood circulation and remove blood stasis, improve the blood stasis and qi stagnation state of the liver cancer microenvironment, possibly inhibit tumor-related fibrosis, and promote drug penetration. E Zha volatile oil (such as β-elemene) also has direct anti-tumor activity. Yanshuo can warm and unblock, "can move blood stasis and qi stagnation, and qi stasis and blood stasis", and is combined with Danshen to enhance the functions of moving qi and promoting blood circulation and pain relief, and is suitable for patients with advanced liver cancer combined with pain. Vinegar Biejia nourishes yin and suppresses yang, softens and resolves, and is traditionally used for accumulation of masses, and its gum components may regulate immunity and inhibit liver cancer cell metastasis. The five drugs are minister drugs and can lead drugs into the liver meridian.

[0017] 3. Auxiliary drug: Baizhu + Fuling, Baihuashexiangcao + Danpi, Baishao + Shanzhu, and Chenpi + Faxia Function: Baizhu + Fuling can tonify the spleen and drain dampness, relieve ascites, lower limb edema, poor appetite, and other symptoms of spleen deficiency and dampness block, and reduce the possible gastrointestinal side effects (such as diarrhea) caused by PD-1 inhibitors. Baihuashexiangcao + Danpi can clear heat and detoxify, cool blood and relieve jaundice, and is suitable for liver cancer combined with damp-heat syndrome (such as jaundice, bitter taste in the mouth), and its active ingredients (such as paeonol) can assist in anti-inflammatory and inhibition of tumor angiogenesis. Baishao + Shanzhu can nourish the liver and kidney, and soothe the liver, and improve the hypochondriac pain caused by liver yin deficiency. Chenpi + Faxia can regulate qi and resolve phlegm, and descend adverse flow and harmonize the stomach, and is aimed at the symptoms of qi stagnation (such as nausea, vomiting, poor appetite, abdominal distension) caused by advanced liver cancer or PD-1 treatment.

[0018] 4. Ministerial drug: Muzegancao Function: harmonize all drugs, moderate and balance, reduce the toxicity of the composition, and protect the gastrointestinal mucosa.

[0019] The efficacy of the traditional Chinese medicine composition in the present application is to invigorate the spleen and soften the liver, remove blood stasis and resolve masses.

[0020] The indications of the traditional Chinese medicine composition in the application: It is suitable for liver cancer patients with syndrome of spleen-Qi deficiency, combined with blood stasis and Qi stagnation, and it is clinically manifested as fatigue, poor sleep and appetite, abdominal distension and pain, jaundice, lower limb edema and the like.

[0021] Modern pharmacology shows that spleen-Qi tonifying drugs (Dangshen, Beiqi, Baishu, Zhigancao and the like) can enhance digestive absorption function, regulate immune state and improve cachexia; blood-activating and stasis-removing drugs (Danshen, E'zhu, Bambooshoot, Danpi and the like) can promote fibrous tissue softening, absorption and dredge of hepatic vascular occlusion, improve liver blood circulation, reduce blood viscosity of malignant tumor patients, improve the "hypercoagulable state" of malignant tumor patients, have antifibrin and fibrinolytic effects, and can prevent or reduce tumor embolism and metastasis and the like; Chubiejia has the effects of anti-liver fibrosis, anti-tumor and immune regulation and the like; Baihuasheshecao can directly act on cancer cells, improve immune function of the body and enhance anti-cancer ability; Paeoniflorin has the protective effect on hepatitis, liver damage and liver fibrosis, and can play a regulating role on the occurrence and development process of liver cancer through various signal pathways, induce apoptosis of liver cancer cells, inhibit liver cell proliferation, block invasion and metastasis; Shanzhuyu has the effect of protecting liver, and its extract Shanzhuyu polysaccharide can inhibit the proliferation of liver cancer HepG2 cells.

[0022] The traditional Chinese medicine composition in the application takes "spleen-Qi tonification as the basis, blood-activating and stasis-removing as the target, and detoxification and knot-dissolving and viscera regulation as the core compatibility principle, forms the prescription characteristics of "simultaneous promotion of healthy energy and elimination of pathogenic factors, treatment of both the root and the branch and multi-target synergism", and specifically embodies as follows: 1. Simultaneous tonification and reduction, and sequential attack and tonification The monarch Dangshen and Beiqi are sweet and warm and can tonify Qi, and can cultivate and tonify the middle warmer, so that the spleen can transport and the healthy energy can recover; the ministers Danshen and E'zhu are acrid and bitter and can pass through and activate blood and remove stasis, and can dredge Qi and blood and make them reach the destination; the aids Baihuasheshecao and Chubiejia are bitter and salty and can detoxify and dissolve knots, and can jointly play the effect of removing stasis and resolving masses. The combination of the drugs makes tonification without stagnation, attack without damage, the healthy energy is filled and the pathogenic factors are eliminated, which embodies the prescription essence of "promoting healthy energy without leaving pathogenic factors and eliminating pathogenic factors without damaging healthy energy".

[0023] 2. Treatment of both symptoms and pathogenesis The prescription deeply understands the principle of "treatment of disease must be based on the root", and directly attacks the pathogenesis by "spleen-Qi tonification and blood-activating". Dangshen and Beiqi are sweet and warm and can enter the spleen and transport the middle warmer, so that the production of Qi and blood is in source; Danshen and E'zhu are acrid and bitter and can activate blood and remove stasis, so that Qi and blood can flow unobstructed. The two are used together to treat the root of spleen deficiency and blood stasis. However, "treatment of the branch in an emergency" cannot be abandoned, so the aids Fuling can slightly penetrate and drain water, Baihuasheshecao and Danpi can clear heat and resolve jaundice, and Yanhusuo and Baishao can soothe the liver and relieve pain. In this way, both the root and the branch are treated, the source of Qi is dredged to recover the healthy energy, and the flow is blocked to relieve the branch in an emergency, so that the pathogenic factors are eliminated and the healthy energy is stable, the pain is reduced and the jaundice is resolved, which is in line with the teaching of "both branches and roots are treated in an emergency, and only the branch is treated in a severe case" in the Canon of Internal Medicine.

[0024] 3. Multi-target synergism, synergistic effect and toxicity reduction (1) Immune regulation: Dangshen and Shihu activate anti-tumor immunity (CD8+ T cells), Danshen and Huaishu inhibit immune escape (Tregs), and synergistically enhance the efficacy of PD-1 inhibitors.

[0025] (2) Vessel regulation: Baihuasheshecao, Chubiejia, and Danshen inhibit the VEGF pathway, promote tumor vessel normalization, and improve drug penetration.

[0026] (3) Organ protection: Laifuzi and Chenpi regulate qi and stomach to reduce gastrointestinal reactions; Baishao and Shanzhuo nourish the liver and yin to prevent liver toxicity and ensure treatment tolerance.

[0027] 4. Integration of modern research and TCM theory (1) Network pharmacology verification: IL-6 and STAT3 are key targets for spleen-tonifying and blood-activating and stasis-removing drugs in the treatment of liver cancer. Components such as luteolin and hederacoside A reverse PD-1 resistance by binding to IL-6 (<-5.0 kcal / mol), scientifically explaining the immune regulation mechanism of the "spleen-tonifying and stasis-removing method".

[0028] (2) Integration of whole and local: both follow the "disease differentiation and treatment" principle of TCM and precisely regulate the tumor microenvironment (TME), embodying the integrated medical approach of "combination of disease and syndrome, and integration of Chinese and Western medicine".

[0029] The traditional Chinese medicine formula in the present invention is based on the framework of "strengthening the body and cultivating the foundation + activating blood and detoxifying + symptomatic treatment and care", and through the balance of drug properties, the combination of disease and syndrome, and the synergy of multiple pathways, it achieves the comprehensive treatment goal of "increasing efficacy, reducing toxicity, and improving prognosis", providing an optimized scheme for liver cancer immunotherapy. Therefore, the present invention also claims the following technical solutions: The present invention provides a traditional Chinese medicine preparation prepared from the above-mentioned traditional Chinese medicine composition.

[0030] As an alternative embodiment, the above-mentioned traditional Chinese medicine preparation is in the form of a paste, a decoction, granules, tablets, or capsules.

[0031] As an alternative embodiment, the preparation method of the above-mentioned traditional Chinese medicine preparation comprises the following steps: S1. Take the above-mentioned traditional Chinese medicine composition, and soak it in drinking water, except for Chubiejia; S2. Cook Chubiejia in drinking water to obtain Chubiejia medicinal liquid; S3. Combine the medicinal materials after soaking in step S1 with the soaking water and the Chubiejia medicinal liquid, and cook them to obtain medicinal liquid; S4. Take the medicinal residues in step S3, and cook them in drinking water to obtain medicinal liquid; S5. Combine the medicinal liquids obtained in steps S3 and S4 to obtain the traditional Chinese medicine preparation; Steps S1 and S2 can be performed simultaneously or in any order.

[0032] As an alternative embodiment, in step S1, the water is added in an amount of 6-10 times (preferably 8 times) the amount of drinking water.

[0033] As an alternative embodiment, in step S1, the soaking time is 20-40 minutes (preferably 30 minutes).

[0034] As an alternative embodiment, in step S2, the water is added in an amount of 4-6 times (preferably 5 times) the amount of water.

[0035] As an alternative embodiment, in step S2, the decoction is done by boiling with high heat and then simmering for 20-40 minutes (preferably 30 minutes).

[0036] As an alternative embodiment, in step S3, the decoction is done by boiling with high heat and then simmering for 40-60 minutes (preferably 50 minutes).

[0037] As an alternative embodiment, in step S4, the water is added in an amount of 4-8 times (preferably 6 times) the amount of water.

[0038] As an alternative embodiment, in step S4, the decoction is done by boiling with high heat and then simmering for 30-50 minutes (preferably 40 minutes).

[0039] As an alternative embodiment, in step S5, the combined medicinal liquid is concentrated to an appropriate volume for consumption (usually 200-300 mL).

[0040] Alternatively, the traditional Chinese medicine decoction can be sterilized by boiling and stored in the refrigerator (≤24 hours). As an alternative embodiment, in the traditional Chinese medicine composition, the vinegar turtle shell is crushed or pounded, and the radix typhonii is prepared with ginger or alum.

[0041] As an alternative embodiment, in the traditional Chinese medicine composition, the radix typhonii is prepared with ginger or alum.

[0042] As an alternative embodiment, the decoction is done in a ceramic sand pot, a glass decoction pot, or a stainless steel pot (iron and aluminum utensils are not recommended).

[0043] As an alternative embodiment, the preparation method of the above traditional Chinese medicine preparation is: S1. Take the above traditional Chinese medicine composition, except for the vinegar turtle shell, and soak it in 6-10 times the amount of drinking water for 20-40 minutes; S2. Add 4-6 times the amount of drinking water to the vinegar turtle shell, boil with high heat, then simmer for 20-40 minutes to obtain a vinegar turtle shell medicinal liquid; S3. Combine the soaked medicinal materials with the soaking water and the vinegar and turtle shell liquid, boil with a strong fire and then change to a weak fire to decoct for 40-60 minutes, filter, and obtain a medicinal liquid; S4. Take the medicinal residues of step S3 and add 4-8 times the amount of drinking water, boil with a strong fire and then change to a weak fire to decoct for 30-50 minutes, filter, and obtain a medicinal liquid; S5. Combine the medicinal liquids obtained in steps S3 and S4 and concentrate to a suitable serving amount (200-300 mL) to obtain a traditional Chinese medicine decoction.

[0044] The application provides application of the above traditional Chinese medicine composition or the above traditional Chinese medicine preparation in preparation of a liver cancer resistant drug.

[0045] The application provides application of the above traditional Chinese medicine composition or the above traditional Chinese medicine preparation in preparation of a product for enhancing the liver cancer treatment effect of a PD-1 inhibitor.

[0046] The application provides application of the above traditional Chinese medicine composition or the above traditional Chinese medicine preparation in preparation of a product for reducing the toxic side effect of a PD-1 inhibitor.

[0047] The application provides a liver cancer treatment drug, which contains the above traditional Chinese medicine composition or the above traditional Chinese medicine preparation and a PD-1 inhibitor.

[0048] As an alternative embodiment, the drug further includes pharmaceutically acceptable pharmaceutical adjuvants.

[0049] As an alternative embodiment, the pharmaceutical adjuvant includes any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, an emulsifying agent, a co-solvent, a surfactant or a buffer.

[0050] As an alternative embodiment, the carrier includes a liposome, a micelle, a dendrimer, a microsphere or a microcapsule.

[0051] As an alternative embodiment, the pharmaceutical adjuvant further includes any one or a combination of at least two of a colorant, a pH regulator, an antioxidant, a bacteriostatic agent.

[0052] The application has the following beneficial effects: The present application provides a traditional Chinese medicine composition for synergistically enhancing the efficacy of PD-1 inhibitors in treating liver cancer and reducing side effects. Animal data show that the combination of the traditional Chinese medicine composition and PD-1 inhibitors can produce significant anti-tumor effects, with significant inhibition of tumor growth, prolongation of the median survival of tumor-bearing mice, and effective improvement of symptoms such as cancer-related fatigue. At the molecular mechanism level, the combination therapy group can significantly down-regulate the expression levels of key tumor-related factors such as VEGF, IL-6 and TNF-α in H22 liver cancer tissues, suggesting that it may play a synergistic role by regulating the tumor microenvironment and inflammatory response. Clinical research data further show that the combination of the traditional Chinese medicine composition and PD-1 inhibitors not only helps to improve the objective response rate (ORR) and improve the clinical symptoms of patients (such as liver pain, fatigue, poor appetite, etc.), thereby improving the quality of life, but also effectively reduces the immune therapy-related adverse reactions (irAEs).

[0053] The traditional Chinese medicine composition of the present application can be prepared into various preparations according to actual needs, has advantages such as easy to carry and store, helps to improve the medication compliance of patients, and is suitable for long-term anti-tumor treatment of liver cancer patients. The traditional Chinese medicine composition of the present application solves the clinical problems of low effective rate and high side effects of PD-1 inhibitor monotherapy through multi-target regulation, provides a safer and more effective solution for immunotherapy of liver cancer, and has good clinical application prospect and popularization value. BRIEF DESCRIPTION OF DRAWINGS

[0054] Figure 1 The food intake measurement results of the mice treated differently in Example 12.

[0055] Figure 2 The water intake measurement results of the mice treated differently in Example 12. DETAILED DESCRIPTION

[0056] The present application is further illustrated in conjunction with the drawings and specific examples of the specification, but the examples do not limit the present application in any form. Unless otherwise specified, the reagents, methods and equipment used in the present application are conventional reagents, methods and equipment in the technical field.

[0057] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0058] Mouse PD-1 inhibitor (InVivoMAb anti-mouse PD-1 (CD279)): purchased from BioXcell, Inc., USA, item number BE0146.

[0059] PBS buffer: purchased from Sivier Biotech Co., Ltd., item number: G0002-2L.

[0060] Example 1 The traditional Chinese medicine composition provided in the embodiment is composed of the following raw materials in parts by mass: Dangshen 20 parts, Beiqi 30 parts, Danshen 15 parts, E'zhu 15 parts, Bayebatza 10 parts, Yansu 15 parts, vinegar Biejia 30 parts, Baizhu 15 parts, Fuling 20 parts, Baihuasheshecao 30 parts, Danpi 10 parts, Baishao 15 parts, Shanzhu 15 parts, Faxia 10 parts, Chenpi 10 parts, and Mugegancao 6 parts.

[0061] Example 2 The traditional Chinese medicine composition provided in the embodiment is composed of the following raw materials in parts by mass: Dangshen 20 parts, Beiqi 30 parts, Danshen 15 parts, E'zhu 15 parts, Bayebatza 10 parts, Yansu 15 parts, vinegar Biejia 20 parts, Baizhu 15 parts, Fuling 20 parts, Baihuasheshecao 30 parts, Danpi 10 parts, Baishao 10 parts, Shanzhu 10 parts, Faxia 10 parts, Chenpi 10 parts, and Mugegancao 5 parts.

[0062] Example 3 The traditional Chinese medicine composition provided in the embodiment is composed of the following raw materials in parts by mass: Dangshen 40 parts, Beiqi 60 parts, Danshen 20 parts, E'zhu 20 parts, Bayebatza 20 parts, Yansu 20 parts, vinegar Biejia 40 parts, Baizhu 30 parts, Fuling 30 parts, Baihuasheshecao 60 parts, Danpi 20 parts, Baishao 20 parts, Shanzhu 20 parts, Faxia 20 parts, Chenpi 15 parts, and Mugegancao 10 parts.

[0063] Example 4 The traditional Chinese medicine composition provided in the embodiment is composed of the following raw materials in parts by mass: Dangshen 30 parts, Beiqi 45 parts, Danshen 15 parts, E'zhu 15 parts, Bayebatza 15 parts, Yansu 15 parts, vinegar Biejia 30 parts, Baizhu 15 parts, Fuling 25 parts, Baihuasheshecao 45 parts, Danpi 15 parts, Baishao 15 parts, Shanzhu 15 parts, Faxia 15 parts, Chenpi 10 parts, and Mugegancao 6 parts.

[0064] Example 5 Preparation of a traditional Chinese medicine decoction for synergistically enhancing the anti-liver cancer efficacy of a PD-1 inhibitor and reducing the toxic side effects 1. Preparation of traditional Chinese medicine materials Take the traditional Chinese medicine composition of Example 1: Dangshen 20 g, Beiqi 30 g, Danshen 15 g, E'zhu 15 g, Bayebatza 10 g, Yansu 15 g, vinegar Biejia 30 g, Baizhu 15 g, Fuling 20 g, Baihuasheshecao 30 g, Danpi 10 g, Baishao 15 g, Shanzhu 15 g, Faxia 10 g, Chenpi 10 g, and Mugegancao 6 g.

[0065] Pretreatment of medicinal materials: vinegar Biejia needs to be separately crushed or pounded to increase the dissolution of effective components. Faxia needs to be processed (such as ginger processing or alum processing) to reduce toxicity.

[0066] 2. Decoction apparatus Select ceramic sand pot, glass decoction or stainless steel pot (iron, aluminum utensils).

[0067] 3. Decoction steps ① Soak: Add medicinal materials (except for Vitikieli) to drinking water and soak for 30 minutes. The water amount should be 3-5 cm higher than the medicinal materials (about 8 times the weight of medicinal materials).

[0068] ② First decoction of Vitikieli: Add Vitikieli to 500 mL of drinking water. Boil over high heat and then simmer over low heat for 30 minutes. Filter out the medicinal liquid for later use.

[0069] ③ First decoction: Combine the soaked medicinal materials with the soaking water and the medicinal liquid of Vitikieli. Boil over high heat and then simmer over low heat while maintaining a slight boiling state for 40-50 minutes. Filter out the medicinal liquid (about 300-400 mL).

[0070] ④ Second decoction: Add 1000-1200 mL of drinking water to the medicinal residue. Boil over high heat and then simmer over low heat for 30 minutes. Filter out the medicinal liquid (about 200-300 mL).

[0071] ⑤ Mixed medicinal liquid: Combine the medicinal liquids from the two decoctions (about 500-700 mL in total) and concentrate to a serving amount of 200-300 mL.

[0072] Example 6: Preparation of a Chinese medicinal decoction that synergistically enhances the efficacy of PD-1 inhibitors against liver cancer and reduces toxic side effects The preparation method of the Chinese medicinal decoction is the same as in Example 5, except that the Chinese medicinal composition of Example 2 is used in the preparation of the medicinal materials.

[0073] Example 7: Preparation of a Chinese medicinal decoction that synergistically enhances the efficacy of PD-1 inhibitors against liver cancer and reduces toxic side effects The preparation method of the Chinese medicinal decoction is the same as in Example 5, except that the Chinese medicinal composition of Example 3 is used in the preparation of the medicinal materials.

[0074] Example 8: Preparation of a Chinese medicinal decoction that synergistically enhances the efficacy of PD-1 inhibitors against liver cancer and reduces toxic side effects The preparation method of the Chinese medicinal decoction is the same as in Example 5, except that the Chinese medicinal composition of Example 4 is used in the preparation of the medicinal materials.

[0075] Example 9: Preparation of a Chinese medicinal paste that synergistically enhances the efficacy of PD-1 inhibitors against liver cancer and reduces toxic side effects Take the traditional Chinese medicine composition, and after being well prepared according to weight parts, soak in 6-8 times the total weight parts of water (not less than 8 hours); heat and decoct the raw materials soaked in water, and sequentially decoct and filter out a decocted medicinal juice, a second decocted medicinal juice and a third decocted medicinal juice, mix all the obtained medicinal juices, and then filter and concentrate to obtain a traditional Chinese medicine clear extract. Steam and melt the glue (preferably tortoise shell glue), pour into the traditional Chinese medicine clear extract, slowly simmer on a small fire, and continuously stir until the extract drops into water and coagulates into beads without scattering. Heat the sugar into a sugar solution, and add into the extract together with crushed walnut kernels when concentrating the extract, and stir well. After the extract cools down, bottle and refrigerate.

[0076] Example 10 Preparation of a traditional Chinese medicine granule for synergistically enhancing the anti-hepatoma effect of a PD-1 inhibitor and reducing toxic side effects Take the traditional Chinese medicine composition, add 8-10 times the amount of water, decoct for 3 hours, filter out the medicinal juice. Add 10 times the amount of water again, decoct for 2.5 hours, filter out the medicinal juice, combine the two decocted liquids, stand still, filter the supernatant, concentrate, cool down, add 2 times the amount of alcohol to the concentrated liquid, stir and precipitate overnight. Take the supernatant, concentrate to a thick extract; add appropriate pharmaceutical aids, granulate, dry, and size to obtain 20 g of granules, which are packed in 10 g per bag.

[0077] Example 11 Preparation of a traditional Chinese medicine tablet or capsule for synergistically enhancing the anti-hepatoma effect of a PD-1 inhibitor and reducing toxic side effects Take the traditional Chinese medicine composition, add 9-11 times the amount of water, decoct for 2-3.5 hours, filter out the medicinal juice. Add 9 times the amount of water again, decoct for 2.5 hours, filter out the medicinal juice, combine the two decocted liquids, stand still, filter the supernatant, concentrate, cool down, add 3 times the amount of alcohol to the concentrated liquid, stir and precipitate overnight. Take the supernatant, concentrate to a thick extract; add pharmaceutical aids, vacuum dry, crush, granulate, and press into tablets or fill into capsules.

[0078] Example 12 Animal experiment Objective of the experiment: To investigate the synergistic anti-tumor effect of the traditional Chinese medicine decoction of the application combined with a PD-1 inhibitor on H22 hepatoma tumor-bearing mice and its potential mechanism of action.

[0079] I. Construction of H22 hepatoma tumor-bearing mouse model 1. Mouse modeling Take 64 BALB / C mice, half male and half female, weighing 18-22 g, SPF level. Take one branch of H22 hepatoma cell strain in a liquid nitrogen tank, place it in a 37°C electric heating constant temperature water bath box, and gently shake it to melt it as soon as possible. Take out the cryopreservation tube, disinfect it with alcohol, open it, and use a pipette to suck out the cell suspension and inject it into a centrifuge tube with the addition of 10% calf serum RPMI-1640 medium. Centrifuge normally to prepare a tumor cell suspension with a tannin blue count of about 1×10 7 cells / ml. Take 0.1 ml (about 1×10 6The tumor cells were inoculated into the abdominal cavity of the mice. After three passages, the tumor was obtained from the white ascites of the mice under sterile conditions. The tumor cell suspension was prepared by adding normal saline to the tumor cells, and about 0.1 ml (about 1 x 10 6 tumor cells) was inoculated into the right armpit of the BALB / C mice.

[0080] 2. Success criteria of the model ① Tumorigenesis time: obvious subcutaneous nodules were touched 5-7 days after inoculation; ② Volume criteria: the tumor diameter reached 5-8 mm (about 100-150 mm 3 ) 10 days after inoculation.

[0081] II. Drugs and their preparation 1. Traditional Chinese medicine stock solution (1) The traditional Chinese medicine composition in Example 5 was pretreated in the same way.

[0082] (2) Decoction extraction ① First extraction The medicinal materials except for Viticellus were mixed with 8 times the amount of deionized water (V / W) and soaked for 30 minutes. Viticellus was added with 5 times the amount of water, and after boiling with strong fire, it was decocted with weak fire for 30 minutes. The soaked medicinal materials and the Viticellus decoction were combined, and after boiling with strong fire, it was decocted with weak fire for 1 hour. Filtration was performed, and the filtrate (filtrate 1) was collected.

[0083] ② Second extraction The residue was added with 6 times the amount of deionized water (V / W), and after boiling with strong fire, it was decocted with weak fire for 40 minutes. Filtration was performed, and the filtrate (filtrate 2) was collected.

[0084] ③ Third extraction The residue was added with 4 times the amount of deionized water (V / W), and after boiling with strong fire, it was decocted with weak fire for 30 minutes. Filtration was performed, and the filtrate (filtrate 3) was collected.

[0085] (3) Concentration All the filtrates (filtrate 1, filtrate 2, and filtrate 3) were combined, and concentrated under reduced pressure (60-70°C) or by rotary evaporation. The concentration was performed to 1.0 g of crude drug / mL (i.e., 1 mL of the concentrated solution is equivalent to 1 g of the original medicinal material).

[0086] (4) Alcohol precipitation purification (optional, to reduce impurities) 95% ethanol was slowly added to the concentrated solution to make the final concentration of ethanol 60%-70%, and stirring was performed while adding. After standing for 12-24 hours (4°C refrigeration), polysaccharides, proteins, and other impurities were precipitated. Centrifugation (3000-4000 rpm, 15 minutes) or filtration was performed, and the supernatant was taken. The supernatant was recovered by reducing pressure, and the remaining medicinal liquid was further concentrated to 1.0 g of crude drug / mL to obtain the traditional Chinese medicine stock solution.

[0087] (5) Sterilization and preservation Sterilization: The drug solution is sterilized by filtering through a 0.22 μm microporous filter or boiling. Preservation: After dispensing, store at 4°C (short-term) or -20°C (long-term).

[0088] 2. Preparation of intragastrically administered drug solution: The daily dose of the traditional Chinese medicine formula for clinical use in humans in the present application is 266 g of crude drug (about 3.8 g of crude drug / kg / day for a 70 kg adult, equivalent to 0.01 g / kg / day for mice according to body surface area conversion (body surface area conversion coefficient 0.0026)). Dilute the concentrated stock solution (1.0 g of crude drug / mL) to 0.001 g / mL, and store the prepared solution in a refrigerator at 4°C for later use.

[0089] 3. Murine PD-1 inhibitor: Prepare a murine PD-1 inhibitor solution using PBS buffer (pH = 7.0), with a solution concentration of 62.95 mg / mL, and use it immediately after preparation.

[0090] III. Experimental grouping and drug administration 1. Randomly divide the tumor-bearing mice into 4 groups (to ensure uniform baseline tumor volume), namely, a model group, a PD-1 group, a traditional Chinese medicine group, and a combination therapy group, with 16 mice in each group. Select 10 non-molded mice as the treatment object for the negative control group. The grouping design is shown in Table 1.

[0091] Table 1. Grouping design of treatment groups

[0092] 2. Specific drug administration regimen (1) Traditional Chinese medicine group Administration method: intragastrical administration (ig); Administration dose: prepared traditional Chinese medicine decoction, 10 mL / kg (containing 0.01 g / kg of crude drug) based on the body weight of the mice; Administration frequency: once a day (qd); Course of treatment: 21 consecutive days; Operation specification: Warm the drug solution to 37°C in a water bath before intragastrical administration, and slowly inject it using a sterile intragastrical needle.

[0093] (2) PD-1 group Administration method: intraperitoneal injection (ip); Administration dose: murine PD-1 inhibitor solution, 0.2 m / each; Administration frequency: once every 3 days (q3d); Course of treatment: a total of 7 times (21-day treatment course); Injection points: choose the left lower abdomen for needle insertion to avoid damaging internal organs.

[0094] (3) Combination therapy group At the same time, receive: Chinese medicine decoction intragastric administration (same as Chinese medicine group scheme) and mouse PD-1 inhibitor solution intraperitoneal injection (same as PD-1 group scheme); Time arrangement: the interval between the two treatments is ≥4 hours.

[0095] (4) Control group Model group: model mice, physiological saline 0.2 mL / once intragastric administration, qd x 21d; Negative control group: unmodeled mice, physiological saline 0.2 mL / once intragastric administration, qd x 21d.

[0096] Four, observation index Primary endpoint: observe the influence of different treatment groups on the growth status, fatigue condition, tumor condition and survival period of H22 liver cancer mice.

[0097] 1. Observation of mouse physical condition: observe and record the physical condition of mice (mouse activity, spirit, change of fur color, etc.) every day.

[0098] 2. Determination of water consumption and food intake of mice: record the changes of water consumption and food intake of mice every day, and draw the curve graph of water consumption and food intake at the end of the experiment.

[0099] 3. Determination of fatigue condition of mice: the fatigue condition of tumor-bearing mice was determined by climbing net test. The mice were placed on a wire mesh with a hole diameter of 1x1 cm perpendicular to the ground, and the duration of the mice gripping on the net was recorded. Each mouse was tested for 3 times with an interval of at least 30 minutes to eliminate the cumulative effect of fatigue, and the average value of the three tests was taken as the result. Mice with tumor diameter of more than 1 cm in right front limb or obviously affecting limb function were excluded and not included in this test.

[0100] 4. Determination of tumor inhibition rate: on the 21st day after modeling, 10 mice in each group were sacrificed by cervical dislocation, and the tumor was completely stripped on ice, the excess tissue was removed, washed with physiological saline and dried with filter paper. The stripped tumor weight was recorded and the tumor inhibition rate was calculated. Tumor inhibition rate (%) = (average tumor weight of model group - average tumor weight of treatment group) / average tumor weight of model group x 100 5. Survival period analysis: another 6 mice were continuously fed and observed until the respiratory and cardiac arrest, and the survival days of mice were recorded for survival period analysis.

[0101] Secondary endpoint: the levels of IL-6, VEGF and TNF-α in tumor tissue were detected by ELISA method to explore the influence of different treatment groups on the levels of tumor-related factors during tumor development.

[0102] Five, experimental results 1. Influence of different administration schemes on the growth status of H22 liver cancer mice Before modeling, the mice in each group showed good physiological state, which was manifested as active spirit, free movement, normal food intake, clean and lustrous fur, red and moist mucosa, clean eye and no secretion, and regular excrement.

[0103] At the early stage of modeling, the physiological state of mice in each group was basically the same as before modeling. With the prolongation of modeling time (about 5-7 days later), the mice in the experimental groups gradually showed obvious pathological characteristics: a gradually increasing subcutaneous mass could be touched at the right axillary of the mice, accompanied by decreased appetite, decreased activity, weight loss, disheveled and dull fur, and abnormal performance such as loose yellow stool.

[0104] After treatment intervention, the clinical symptoms of mice in each treatment group were improved to different degrees. The results of water and food intake determination of mice are shown in Tables 1 and 2. Figure 1 and Figure 2 The results showed that, compared with the model group, the mental state of mice in the PD-1 group and the traditional Chinese medicine group improved significantly, the symptoms such as shivering and curling, disheveled and withered fur were alleviated, and the food and water intake increased. Among them, the activity of mice in the PD-1 group was better than that in the traditional Chinese medicine group. The combination therapy group (PD-1+ traditional Chinese medicine) showed the best therapeutic effect, and the mental state and food and water intake of mice in this group improved most significantly, which were significantly better than those in each single drug treatment group.

[0105] 2. Effect of different administration schemes on fatigue of H22 liver cancer mice The results are shown in Table 2. The results showed that the climbing net test was used to determine the fatigue of tumor-bearing mice. The climbing net duration of mice in the model group was significantly shorter than that in each treatment group (all P<0.05), indicating that tumor load significantly reduced the exercise tolerance of mice. Among the treatment groups, the combination therapy group showed the best anti-fatigue effect, and the climbing net duration was significantly longer than that in the two single drug treatment groups (all P<0.05); there was no significant difference between the PD-1 group and the traditional Chinese medicine group (P>0.05). It is suggested that the combination of PD-1 inhibitor and traditional Chinese medicine can significantly improve tumor-related fatigue through synergistic mechanism, which is better than single therapy.

[0106] Table 2. Climbing net test results of each group

[0107] Note: *compared with the model group and each single drug treatment group, P<0.05, n is the number of mice 3. Effect of different administration schemes on tumor growth of H22 liver cancer mice The experimental results are shown in Table 3, and the results show that each treatment group shows a significant tumor inhibition effect compared with the model group (all P<0.05). The combined treatment group shows the best tumor inhibition effect, with a tumor inhibition rate of 60.54%, which is significantly higher than that of the PD-1 group and the traditional Chinese medicine group (all P<0.05). The tumor inhibition rate of the PD-1 group is significantly higher than that of the traditional Chinese medicine group (P<0.05). It is suggested that the combination of PD-1 and traditional Chinese medicine may enhance the tumor inhibition effect through synergistic effect.

[0108] Table 3 Comparison of tumor inhibition rates of each group

[0109] Note: * Compared with the model group and each single drug treatment group, P<0.05, n is the number of mice 4, Effect of different administration schemes on the survival time of H22 liver cancer mice The survival analysis shows that the median survival time of mice in each group is: 24.5 days in the model group, 34.5 days in the PD-1 group, 29.5 days in the traditional Chinese medicine group, and 42.5 days in the combined treatment group. The combined treatment group shows the most significant survival benefit, and compared with the other three groups, all P<0.05; the PD-1 group and the traditional Chinese medicine group are significantly better than the model group (all P<0.05), and the difference between the two single drug groups is not statistically significant (P>0.05). The combination of PD-1 inhibitor and traditional Chinese medicine treatment can produce a significant synergistic effect, and its survival benefit is better than single therapy.

[0110] 5, Effect of different administration schemes on the VEGF, TNF-α, IL-6 levels of H22 liver cancer mice The determination results of tumor-related factors in each group are shown in Table 4. Compared with the model group, each treatment group can significantly reduce the level of inflammatory factors (compared with the model group, all P<0.05); the effect of the combined treatment group is significantly better than that of the single drug treatment (all P<0.05); there is no statistical difference between the two single drug schemes (P>0.05).

[0111] The combination of PD-1 inhibitor and traditional Chinese medicine shows a significant synergistic effect, and this synergistic effect may be achieved through the following mechanisms: 1) Multi-target regulation of tumor microenvironment, especially significant inhibition of key inflammatory factors such as IL-6; 2) Down-regulation of VEGF expression, reduction of inhibition of tumor angiogenesis, and promotion of vascular normalization. These mechanisms work together, which may be an important mechanism for improving tumor-related symptoms (such as fatigue) and enhancing tumor inhibition effect.

[0112] Table 4 Comparison of tumor-related factors of each group (mean ± standard deviation)

[0113] Note: * Compared with the model group and each single drug treatment group, P<0.05, n is the number of mice Example 13 Clinical study I. Subjects and methods 1. Study subjects: 60 patients with primary liver cancer who were admitted to our hospital for immunotherapy were collected. According to whether they were willing to take the traditional Chinese medicine decoction of the application, they were divided into a treatment group (taking the traditional Chinese medicine decoction of the application) and a control group, with 30 cases in each group.

[0114] 2. Inclusion criteria: patients with advanced primary liver cancer (BCLC B / C stage) diagnosed by clinical or pathological diagnosis, with an immunotherapy course of more than 4 cycles; age 18-75 years old; Eastern Cooperative Oncology Group Performance Status (ECOG PS) score 0-1, Child-Pugh A / B grade, and expected survival period more than 3 months.

[0115] 3. Exclusion criteria: combined with autoimmune diseases or long-term use of immunosuppressive agents; combined with severe primary diseases of cardiovascular, liver, kidney, hematopoietic system, etc. and patients with mental illness; pregnant or lactating women.

[0116] 4. Treatment plan: all patients in the group were treated with immunotherapy for more than 4 cycles (according to the condition, or combined with targeted therapy, interventional therapy, etc.). The control group did not take traditional Chinese medicine, and the treatment group took the traditional Chinese medicine decoction of the application. The traditional Chinese medicine was decocted to 200 ml and taken warm. One dose per day, starting on the day of immunotherapy, and lasting for 7 days per cycle. This intervention lasted for 4 ICIs treatment cycles, and the efficacy was evaluated after 4 treatment cycles.

[0117] 5. Observation index: select two time points before and after treatment (4 treatment cycles): perform liver CT, MRI or color Doppler ultrasound examination, refer to the solid tumor clinical efficacy evaluation standard (RECIST Version 1.1) for efficacy evaluation, and calculate the objective response rate (ORR); refer to the symptom grading and quantification table of primary liver cancer in the Guiding Principles for Clinical Research on New Drugs of Traditional Chinese Medicine, for TCM syndrome efficacy determination; refer to the Quality of Life Scale for Liver Cancer Patients QOL-LC V2.0 (QOL-LC V2.0), to evaluate the quality of life of patients; according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0) of the National Cancer Institute, record irAEs and grade distribution according to organ system, and calculate the incidence of irAEs.

[0118] (1) Objective response rate (ORR) According to RECIST 1.1 criteria, tumor efficacy is divided into the following grades: complete remission (CR): all target lesions disappear, maintain for ≥4 weeks; partial remission (PR): the sum of the longest diameters of target lesions is reduced by ≥30%; stable disease (SD): the change does not reach the PR or PD standard; progressive disease (PD): the sum of target lesions is increased by ≥20% or new lesions appear.

[0119] Calculation formula: objective response rate (ORR) = (CR + PR) / total number of cases x 100%.

[0120] (2) TCM symptom efficacy The TCM symptom efficacy evaluation standard refers to the Primary Liver Cancer Symptom Grading and Quantification Table in the 2002 edition of the Guiding Principles for Clinical Research on New Drugs of Traditional Chinese Medicine. The symptom score is as follows: 0 points for no symptoms, 1 point for mild symptoms, 2 points for moderate symptoms, and 3 points for severe symptoms. The total symptom scores before and after 4 treatment cycles are observed and recorded for both groups before and after treatment.

[0121] Calculation method (nimodipine method): efficacy index = (total score before treatment - total score after treatment) / total score before treatment. Significant improvement (markedly effective): efficacy index (decrease in score) ≥ 70%; partial improvement (effective): efficacy index (decrease in score) ≥ 30%, < 70%. No improvement (ineffective): efficacy index (decrease in score) < 30%.

[0122] Total effective rate = (number of cases with significant effect + number of cases with effect) / total number of cases x 100%.

[0123] (3) Quality of life score (QOL-LC V2.0) The QOL-LC V2.0 for Liver Cancer Patients is used to guide patients to score before and after 4 treatment cycles. The QOL-LC V2.0 for Liver Cancer Patients contains 22 items, covering four areas: physical function (PH area), psychological function (PS area), symptoms (ST area), and social function (SO area). The scoring methods for each area and the total score of quality of life are internationally standardized.

[0124] (4) Immune-related adverse reactions (irAEs) According to the Common Terminology Criteria for Adverse Events (CTCAE v5.0) of the National Cancer Institute of the United States, irAEs are classified by severity as follows: G1 (mild): no symptoms or mild symptoms; only clinical or diagnostic findings; no treatment required. G2 (moderate): symptoms, mild impact on daily life activities; local or non-invasive treatment required (such as oral hormones). G3 (severe): severe symptoms, limiting daily life activities or self-care ability; hospitalization or invasive treatment required (such as intravenous hormone injection). G4 (life-threatening): extremely severe symptoms, causing life-threatening (such as immune myocarditis, severe hepatitis). Emergency rescue (such as ICU monitoring) is required. G5 (death): death directly related to irAEs.

[0125] Toxicity type record: classified statistics by organ system (skin, endocrine, liver, etc.): skin toxicity (such as rash, itching), endocrine toxicity (such as thyroid dysfunction, pituititis), liver toxicity (such as transaminase elevation), lung toxicity (such as pneumonia), and others (such as colitis, myocarditis). The irAEs in each group are classified by grade (G1-G5).

[0126] Calculation formula: irAEs incidence = percentage of cases with irAEs out of total cases.

[0127] II. Results analysis 1. Comparison of TCM syndrome efficacy The experimental results are shown in Table 5. The TCM syndrome effective rate of the treatment group was 96.7%, and that of the control group was 76.7%. The difference between the two groups was statistically significant (P<0.05), indicating that the TCM syndrome efficacy of the treatment group was better than that of the control group.

[0128] Table 5 Comparison of TCM syndrome efficacy (unit: cases)

[0129] Note: * compared with the control group, P<0.05 2. Comparison of QOL-LC V2.0 scale scores The comparison results of QOL-LC V2.0 scale scores are shown in Table 6. Before treatment, there was no statistically significant difference (P>0.05) in the scores of the five domains of QOL-LC V2.0 scale between the two groups. P After treatment, the scores of the treatment group were higher than those of the control group (P<0.05); there was no significant change in the social function domain scores of the two groups, and there was no statistically significant difference (P>0.05) between the two groups. P P Table 6 Comparison of QOL-LC V2.0 scale scores (mean ± standard deviation, unit: points)​​

[0130] Note: * Compared with the control group, P<0.05 3. Comparison of solid tumor efficacy The experimental results are shown in Table 7, and the results show that the ORR rate (CR+PR) of the treatment group is 76.7%, and that of the control group is 53.3%, and the comparison between the two groups has statistical significance (P<0.05), indicating that the treatment group is superior to the control group in terms of efficacy. Table 7 Comparison of solid tumor efficacy (unit: cases)

[0131] Note: * Compared with the control group, P<0.05 4. Comparison of immune-related adverse reactions The results are shown in Table 8, and the results show that after 4 cycles of observation, the incidence of immune toxicity in the treatment group is 3.3%, and that in the control group is 23.3%, and the comparison between the two groups has statistical significance (P=0.02, P<0.05), indicating that the toxicity risk of the treatment group is significantly lower than that of the control group. There was 1 case of immune toxicity in the treatment group, which was G1 skin toxicity; there were 7 cases of immune toxicity in the treatment group, and the adverse reactions mainly occurred in the skin, endocrine, lung, liver and other systems, and were G1-G2 toxicity. Table 8 Comparison of cumulative incidence of immune toxicity (unit: cases)

[0132] Note: * Compared with the control group, P<0.05 This study shows that the combination of traditional Chinese medicine formula and immunotherapy in the present application can significantly improve the objective remission rate (76.7% vs 53.3%) of patients with advanced liver cancer, improve traditional Chinese medicine syndromes (effective rate 96.7% vs 76.7%) and quality of life (psychological, physical function and other scores significantly improved), while reducing the incidence of immune-related adverse reactions (3.3% vs 23.3%), confirming the synergistic advantages of the regimen in terms of efficacy and toxicity reduction.

[0133] Example 14 Typical case To more intuitively show the clinical efficacy and safety of the combination of traditional Chinese medicine composition and PD-1 inhibitor in the treatment of liver cancer in the present application, the following gives a typical case and the efficacy of treatment.

[0134] I. Typical case 1: Li, male, 58 years old

[0135] Medical history: 10 years of history of hepatitis B cirrhosis, without regular antiviral treatment. In May 2023, hepatocellular carcinoma (HCC) was diagnosed, BCLC stage B: tumor size 5.2x4.8 cm (right lobe), portal vein branch thrombus, no distant metastasis.

[0136] Prior treatment: TACE treatment once (in June 2023), and the efficacy evaluation was SD (stable disease), and then transferred to immune + targeted maintenance treatment.

[0137] Treatment regimen: ① Immunotherapy: Sindili monoclonal antibody (200 mg intravenous infusion, once every 3 weeks) + Ruvati (8 mg / d, continuous use). ② Traditional Chinese medicine intervention: the traditional Chinese medicine decoction (the traditional Chinese medicine composition in Example 1) of the present application, one dose per day, decocted with water and taken orally twice. Start taking on the day of immunotherapy, and continue for 7 days per cycle, and take for 4 consecutive cycles. ③ Supportive treatment: antiviral and symptomatic liver protection with Entecavir.

[0138] Efficacy evaluation (after 4 cycles): ① Imaging changes: MRI review showed that the tumor was reduced to 3.1 x 2.9 cm (reduced by about 40%), and the portal vein thrombus was retracted. → RECIST 1.1 standard evaluation was PR (partial remission).

[0139] ② Symptom improvement: Before treatment: fatigue, abdominal distension, poor appetite, and hypochondriac pain (NRS 5 points).

[0140] After treatment: physical recovery (ECOG score 1→0), increased appetite, and pain score decreased to 1 point.

[0141] ③ Safety: No adverse reactions such as skin rash, immune-related hepatitis / pneumonia, etc. occurred.

[0142] ④ Blood routine, liver and kidney function remained stable, and no traditional Chinese medicine related toxicity was found.

[0143] Case 2: Wang, female, 62 years old.

[0144] Medical history: 8 years of hepatitis B history, 5 years of cirrhosis. Diagnosed with hepatocellular carcinoma (HCC) in March 2024, BCLC stage C: multiple intrahepatic lesions (maximum diameter 6.5 cm), combined with lung metastasis.

[0145] Prior treatment: The patient refused interventional therapy. Initially, the target immune combination regimen was used: cari Li Zhu single antibody (200 mg intravenous infusion, once every 3 weeks) combined with Ruvati (8 mg / d, continuous use). One week after treatment, grade III thrombocytopenia (platelet count decreased to 45 x 10 9 / L) occurred, so Ruvati was stopped, and the regimen was adjusted to cari Li Zhu single antibody maintenance treatment.

[0146] Treatment regimen: ① Immunotherapy: Karlizumab (200 mg intravenous infusion, once every 3 weeks). ② Traditional Chinese medicine intervention: The traditional Chinese medicine decoction (the traditional Chinese medicine composition in Example 4) is taken orally, one dose per day, decocted with water and taken twice a day. It is taken from the day of immunotherapy, and each cycle lasts for 7 days, and is taken for 4 consecutive cycles. ③ Supportive treatment: Entecavir dispersible tablets for antiviral treatment, and furosemide for diuresis to control ascites.

[0147] Efficacy evaluation (after 4 cycles): ① Imaging evaluation: After 4 cycles of treatment, the enhanced CT of the abdomen showed that the maximum lesion in the liver was reduced from 6.5 cm to 4.5 cm (about 31% reduction), and the number of lung metastases was reduced. According to the RECIST 1.1 standard, it is evaluated as partial remission (PR).

[0148] ② Improvement of clinical symptoms: Before treatment: severe fatigue (ECOG score 2 points), moderate ascites, and severe loss of appetite (daily food intake < 500 kcal).

[0149] After treatment: physical condition improved significantly (ECOG score 0 points), ascites decreased significantly (no need for continuous use of diuretics), and appetite recovered well (daily food intake > 1200 kcal).

[0150] ③ Safety evaluation: Only grade 1 rash (CTCAE v5.0 classification) occurred during treatment, which was relieved after local external use of glucocorticoid ointment, and no serious adverse events such as immune-related hepatitis or pneumonia occurred.

[0151] ④ Changes in laboratory indicators: Liver function: ALT decreased from 85 U / L before treatment to 37 U / L (normal range); albumin increased from 28 g / L to 35 g / L; platelet count remained within the normal range (125-150 x 10 9 / L).

[0152] III. Typical case 3: Zhang, male, 45 years old.

[0153] Medical history: Chronic hepatitis B virus infection and cirrhosis for many years, without standard antiviral and systemic treatment. In November 2023, he was diagnosed with hepatocellular carcinoma (HCC) by enhanced MRI and alpha-fetoprotein (AFP) examination, and the BCLC clinical stage was B: imaging showed a single occupying lesion in the right lobe of the liver (4.8 cm in diameter), without signs of portal vein or hepatic vein invasion.

[0154] Treatment regimen: ① Immune combination targeted therapy: atezolizumab (1200 mg intravenous infusion) + bevacizumab (15 mg / kg intravenous infusion), once every 3 weeks. ② Traditional Chinese medicine intervention: the traditional Chinese medicine decoction (the traditional Chinese medicine composition in Example 3) of the present application, one dose per day, decocted with water and taken orally twice a day. Start taking on the day of immunotherapy, and continue for 7 days per cycle, and take for 4 consecutive cycles. ③ Supportive treatment: polyene phosphatidylcholine capsules for oral administration for liver protection, entecavir for antiviral treatment, and nutritional support.

[0155] Efficacy evaluation (after 4 cycles): ① Imaging changes: MRI showed that the tumor was reduced to 2.6 cm (reduced by about 46%), and the RECIST 1.1 standard evaluation was PR (partial remission).

[0156] ② Symptom improvement: Before treatment: moderate liver pain (NRS 4 points), difficulty falling asleep (PSQI score 12 points), and obvious anxiety symptoms.

[0157] After treatment: pain was significantly relieved (NRS score decreased to 1 point), sleep quality was significantly improved (PSQI score decreased to 6 points), and mood tended to be stable.

[0158] ③ Safety: No common adverse reactions of bevacizumab (such as hypertension, proteinuria, etc.) occurred; immune therapy-related adverse reactions were all grade 1 (CTCAE v5.0), manifested as transient fatigue, which did not affect the treatment process; liver function indicators remained stable.

[0159] ④ Quality of life: The assessment using the "Liver Cancer Patient Quality of Life Scale QOL-LC V2.0" showed that the total score increased from 58 points before treatment to 82 points, and the improvement in the fields of physical function and psychological function was particularly significant.

[0160] The above examples are preferred embodiments of the present application, but the embodiments of the present application are not limited by the above examples, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application are equivalent replacement methods and are included in the protection scope of the present application.

Claims

1. A traditional Chinese medicine composition, characterized in that, The raw materials include the following by weight: Dangshen 20-40 parts, Beixu 30-60 parts, Danshen 10-20 parts, E Zhi 10-20 parts, Bayazha 10-20 parts, Yanhusuo 15-20 parts, vinegar Biejia 20-40 parts, Baizhu 15-30 parts, Fuling 20-30 parts, Baihuasheshecao 30-60 parts, Danpi 10-20 parts, Baishao 10-20 parts, Shanzhu 10-20 parts, Faxia 10-20 parts, Chenpi 10-15 parts, and moeigancao 5-10 parts.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The raw materials include the following by weight: Dangshen 20-30 parts, Beixu 30-45 parts, Danshen 10-20 parts, E Zhi 10-20 parts, Bayazha 10-20 parts, Yanhusuo 15-20 parts, vinegar Biejia 20-40 parts, Baizhu 15-30 parts, Fuling 20-30 parts, Baihuasheshecao 30-45 parts, Danpi 10-20 parts, Baishao 10-20 parts, Shanzhu 10-20 parts, Faxia 10-20 parts, Chenpi 10-15 parts, and moeigancao 5-10 parts.

3. A traditional Chinese medicine preparation, characterized in that, Prepared from the traditional Chinese medicine composition of claim 1 or 2.

4. Use of the traditional Chinese medicine composition of claim 1 or 2 or the traditional Chinese medicine preparation of claim 3 in the preparation of a drug for resisting liver cancer.

5. Use of the traditional Chinese medicine composition of claim 1 or 2 or the traditional Chinese medicine preparation of claim 3 in the preparation of a product for enhancing the efficacy of a PD-1 inhibitor in resisting liver cancer.

6. Use of the traditional Chinese medicine composition of claim 1 or 2 or the traditional Chinese medicine preparation of claim 3 in the preparation of a product for reducing the toxicity and side effects of a PD-1 inhibitor.

7. A medicament for treating liver cancer, characterized by comprising the compound according to claim 1. The product contains the traditional Chinese medicine composition of claim 1 or 2 or the traditional Chinese medicine preparation of claim 3 and a PD-1 inhibitor.

8. The medicament according to claim 7, characterized in that, The drug further includes a pharmaceutically acceptable pharmaceutical adjuvant.

9. The medicament according to claim 8, characterized in that, The pharmaceutical adjuvant includes any one or a combination of at least two of a carrier, a diluent, an excipient, a filler, a binder, a wetting agent, an emulsifier, a solubilizer, a surface active agent, or a buffer.

10. The medicament according to claim 9, characterized in that, The pharmaceutical adjuvant further includes any one or a combination of at least two of a coloring agent, a pH regulator, an antioxidant, or a bacteriostatic agent.

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